Multiple sclerosis (MS) is the major inflammatory disease of the central nervous system in humans. Both environmental and genetic factors contribute to what is believed to be primarily an immunopathologic etiology. Although environmental factors are important in disease pathogenesis, they can only exert their effects in genetically permissive hosts. Identification and molecular characterization of disease susceptibility genes in experimental allergic encephalomyelitis (EAE), the principle animal model of MS, will lead to a better understanding of the interplay between such factors in the immunopathologic pathways leading to disease. By extension, the investigators propose that homologous genes, or other genes in the pathways to which they belong, will also be relevant in susceptibility to MS. The long-term goal of the research proposed in this application is to characterize the immunoregulatory genes that govern the phenotypic expression of EAE in the mouse. To isolate, identify, and study these genes, they must first be precisely located on the chromosomes encoding them, this is best achieved using molecular genome exclusion mapping with DNA-based markers. During the previous funding period this approach allowed the investigators to identify binary and quantitative trait loci that control EAE susceptibility and the clinical and histopathologic parameters of the disease. Additionally, they identified unique disease subtypes that correlate with the clinical courses of human MS and recapitulated the sexual dimorphisms seen. Substantial progress was also made toward the positional cloning of Bphs, an autoimmune disease susceptibility locus common to both EAE and autoimmune orchitis. In this renewal application they will: 1) establish reciprocal, phenotype selected congenic lines between SJL/J and B10.S/DvTe mice and simultaneously do multi-generational backcross linkage analysis to verify and extend their analysis of the EAE loci identified in genome scans and 2) complete the positional cloning of Bphs.